3-amino-pyridine derivatives for the treatment of metabolic disorders

ABSTRACT

Compounds represented by the general formula (I): 
     
       
         
         
             
             
         
       
     
     pharmaceutically acceptable salts or solvates thereof, a process for their manufacture; pharmaceutical compositions containing them; and use of the compounds in the treatment of metabolic disorders related to insulin resistance or hyperglycemia are described.

The present application is a divisional of U.S. patent application Ser.No. 12/441,891 filed on Mar. 18, 2009, which claims priority from PCTPatent Application No. PCT/IB2007/053817 filed on Sep. 20, 2007, whichclaims priority from U.S. Provisional Patent Application Ser. Nos.60/846,194 and 60/875,672 filed on Sep. 21, 2006, and Dec. 18, 2006,respectively, the disclosures of which are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to compounds that are useful in treatingmetabolic disorders related to insulin resistance or hyperglycemia.

BACKGROUND OF THE INVENTION

Excessive weight, and in extreme cases obesity, is a widespread medicalproblem. This may be due in part to sedentary life styles and poor diet(high in fats and carbohydrates), as well as to a genetic predispositionin many cases. Obesity is a well-known risk factor for hypertension,Type 2 diabetes and cardiovascular diseases.

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Often abnormal glucose homeostasis is associated bothdirectly and indirectly with alterations of the lipid, lipoprotein andapolipoprotein metabolism and other metabolic and hemodynamic disease.Therefore patients with Type 2 diabetes mellitus are at especiallyincreased risk of macrovascular and microvascular complications,including coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Therefore,therapeutic control of glucose homeostasis, lipid metabolism andhypertension are critically important in the clinical management andtreatment of diabetes mellitus. There are two generally recognized formsof diabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus(IDDM), patients produce little or no insulin, the hormone thatregulates glucose utilization. In Type 2 diabetes, or non-insulindependent diabetes mellitus (NIDDM), patients often have plasma insulinlevels that are the same or even elevated compared to nondiabeticsubjects; however, these patients have developed a resistance to theinsulin stimulating effect on glucose and lipid metabolism in the maininsulin-sensitive tissues, which are muscle, liver and adipose tissues,and the plasma insulin levels, while elevated, are insufficient toovercome the pronounced insulin resistance. Both obesity and Type 2diabetes are characterized by peripheral tissue insulin resistance.

The prevalence of insulin resistance in glucose intolerant subjects haslong been recognized. Reaven et al (American Journal of Medicine, 60,80, 1976) used a continuous infusion of glucose and insulin(insulin/glucose clamp technique) and oral glucose tolerance tests todemonstrate that insulin resistance existed in a diverse group ofnonobese, nonketotic subjects. These subjects ranged from borderlineglucose tolerant to overt, fasting hyperglycemia. The diabetic groups inthese studies included both insulin dependent (Type 1) and noninsulindependent (Type 2) subjects.

Coincident with sustained insulin resistance is the more easilydetermined hyperinsulinemia, which can be measured by accuratedetermination of circulating plasma insulin concentration in the plasmaof subjects. Hyperinsulinemia can be present as a result of insulinresistance, such as is in obese and/or diabetic (Type 2) subjects and/orglucose intolerant subjects, or in Type 1 subjects, as a consequence ofoverdose of injected insulin compared with normal physiological releaseof the hormone by the endocrine pancreas.

The independent risk factors such as obesity and hypertension foratherosclerotic diseases are also associated with insulin resistance.Using a combination of insulin/glucose clamps, tracer glucose infusionand indirect calorimetry, it has been demonstrated that the insulinresistance of essential hypertension is located in peripheral tissues(principally muscle) and correlates directly with the severity ofhypertension (Diabetes Care, 14, 173, 1991). In hypertension of theobese, insulin resistance generates hyperinsulinemia, which is recruitedas a mechanism to limit further weight gain via thermogenesis, butinsulin also increases renal sodium reabsorption and stimulates thesympathetic nervous system in kidneys, heart, and vasculature, creatinghypertension.

It is now appreciated that insulin resistance is usually the result of adefect in the insulin receptor signaling system, at a site post bindingof insulin to the receptor. Accumulated scientific evidencedemonstrating insulin resistance in the major tissues which respond toinsulin (muscle, liver, adipose), strongly suggests that a defect ininsulin signal transduction resides at an early step in this cascade,specifically at the insulin receptor kinase activity, which appears tobe diminished (Diabetalogia, 34, 848, 1991).

In the recent past, a new class of drugs, which act by reducingperipheral insulin resistance has been developed. These drugs areligands for the nuclear receptor, peroxisome proliferator-activatedreceptor gamma isoform (PPAR gamma), expressed primarily in the adiposetissue. These drugs act as insulin sensitizers in reducing blood sugarand hyperinsulinemia. The most common side effects of these PPAR gammaactivators are weight gain, edema, increased risk of stroke and heartattack.

Diabetic patients are at an increased risk of developing cardiovasculardisease events due to risk factors such as dyslipidemia, obesity,hypertension, glucose intolerance. The presence of the above riskfactors in an individual is collectively called metabolic syndrome.According to National Cholesterol Expert Panel's ATP III criteria,dyslipidemia is defined as a state in which an individual exhibits acombination of triglyceride levels of 150 mg/dl and above and HDL,cholesterol level of less than 40 mg/dl in men and less than 50 mg/dl inwomen. (J. Am. Med. Association, 285, 2486-2497, 2001).

U.S. Pat. No. 6,583,157 discloses quinolinyl and benzothiazolylcompounds as PPAR modulators.

U.S. Pat. No. 6,403,607 discloses sulfonamide derivatives exhibitingeffects in the treatment of peptic ulcer and a drug comprising thederivative as an active ingredient.

U.S. Pat. No. 6,262,112 and U.S. Pat. No. 6,573,278 disclose arylsulfonamides and analogues and their use in the treatment ofneurodegenerative diseases.

There is a need for improved and alternative medicaments for thetreatment of metabolic disorders related to insulin resistance orhyperglycemia.

SUMMARY OF THE INVENTION

The present invention provides compounds represented by the generalformula (I):

wherein:

-   -   Ar is a quinoline or isoquinoline moiety which is substituted or        unsubstituted;    -   B is —O—, —S—, or —NH—;    -   R¹ is hydrogen or S(CO)₂R⁴;    -   R² is S(O)₂R⁴, C(O)OR⁵, or C(O)(CH₂)_(n)—C(O)OR⁶;    -   R³ is halogen, cyano, C(O)OR⁷ or C(O)NR⁸R⁹;    -   R⁴ is aryl:    -   R⁵ is (C₁-C₆)alkyl or aryl;    -   R⁶ is hydrogen, (C₁-C₄)alkyl, or aryl;    -   R⁷ is hydrogen or (C₁-C₄)alkyl;    -   R⁸ and R⁹ are independently hydrogen or (C₁-C₆)alkyl; and    -   n is an integer from 1-3; and

their pharmaceutically acceptable salts and solvates.

The present invention also relates to a process for the preparation ofthe compounds of formula (I) their pharmaceutically acceptable salts,their pharmaceutically acceptable solvates and pharmaceuticalcompositions containing them.

The present invention relates to compounds of general formula (I) thatare useful in treating metabolic disorders related to insulin resistanceor hyperglycemia, methods employing such compounds, and use of suchcompounds.

According to another aspect of the present invention, there are providedmethods for manufacture of medicaments including compounds of generalformula (I), which are useful for the treatment of metabolic disordersrelated to insulin resistance or hyperglycemia.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Listed below are definitions, which apply to the terms as they are usedthroughout the specification and the appended claims (unless they areotherwise limited in specific instances), either individually or as partof a larger group.

The term “alkyl,” means, unless otherwise stated, a straight or branchedchain, or cyclic hydrocarbon radical, or combination thereof, which maybe fully saturated, mono- or polyunsaturated, having from one to eightcarbon atoms. Examples of saturated hydrocarbon radicals include groupssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and thelike. An unsaturated alkyl group is one having one or more double bondsor triple bonds. Examples of unsaturated alkyl groups include vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thelike.

Unless stated otherwise, alkyl groups can be unsubstituted orsubstituted by one or more identical or different substituents. Any kindof substituent present in substituted alkyl residues can be present inany desired position provided that the substitution does not lead to anunstable molecule. A substituted alkyl refers to an alkyl residue inwhich one or more, for example, 1, 2, 3, 4 or 5 hydrogen atoms arereplaced with substituents, for example alkyl, halogen, hydroxyl, acyl,carboxyl, alkoxyl, ester, amino, amido, acetamido, fluoroalkyl, aralkyl,acyloxy, aryl, heteroaryl, heterocyclyl, and the like.

As used herein, the term “alkoxyl” or “alkoxy” refers to an alkyl grouphaving an oxygen radical attached thereto, wherein alkyl is as definedabove. The terms include, therefore, alkoxyl or alkoxy groups which aresubstituted by one or more identical or different groups. Representativealkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy,tert-butoxy group.

As used herein, the term “acyl” refers to any group or organic radicalsuch as alkyl (which can be further substituted with an alkyl, alkoxy,cycloalkylamino, hydroxy or halo) attached to a carbonyl group, whereinalkyl is as defined above.

The term “heteroatom” refers to nitrogen, oxygen and sulfur. It shouldbe noted that any heteroatom with unsatisfied valences is assumed tohave a hydrogen atom to satisfy the valences.

As used herein, the term “aryl” refers to a monocyclic or bicyclicaromatic ring having up to 10 ring carbon atoms. Examples of arylinclude phenyl, naphthyl, biphenyl and the like. Unless statedotherwise, aryl residues, for example phenyl or naphthyl, can beunsubstituted or optionally substituted by one or more substituents, forexample, up to five identical or different substituents selected fromthe group consisting of halogen, alkyl, fluoroalkyl, hydroxyl, alkoxytrifluoromethoxy; cyano, amide, CH₃CONH—, acyl, carboxyl, —COOH,sulfonyl, aryl, heteroaryl and a heterocyclyl group.

Aryl residues can be bonded via any desired position, and in substitutedaryl residues, the substituents can be located in any desired position.For example, in monosubstituted phenyl residues the substituent can belocated in the 2-position, the 3-position, the 4-position or the5-position. If the phenyl group carries two substituents, they can belocated in 2,3-position, 2,4-position, 2,5-position, 2,6-position,3,4-position or 3,5-position.

The term “heteroaryl” means, unless other wise stated, aryl groups thatcontain from one to four heteroatoms selected from N, O and S. The ringheteroatoms can be present in any desired number and in any positionwith respect to each other provided that the resulting heteroaryl systemis stable.

Non-limiting examples of heteroaryl groups include pyrrolyl, pyrazolyl,imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl,pyridyl, pyrimidyl, benzothiazolyl, benzimidazolyl, benzooxazolyl,quinolyl, isoquinolyl, quinoxalinyl, and the like.

The terms “heterocyclyl”, “heterocyclic” “heterocycle” and “heterocyclo”refer to a saturated, or partially unsaturated monocyclic or bicyclicring system containing 3, 4, 5, 6, 7, 8, 9, 10 or 11, 12, 13 or 14 ringatoms of which 1, 2, 3 or 4 are identical or different heteroatomsselected from: nitrogen, oxygen and sulfur. The heterocyclyl group may,for example, have 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms and/or1 to 4 nitrogen atoms in the ring. Monocyclic heterocyclyl groupsinclude 3-membered, 4-membered, 5-membered, 6-membered and 7-memberedrings. Suitable examples of such heterocyclyl groups are, piperidinyl,piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, azepanyland the like.

Bicyclic heterocyclyl groups can include two fused rings, one of whichis a 5-, 6- or 7-membered heterocyclic ring and the other of which is a5-, or 6-membered carbocyclic or heterocyclic ring. Exemplary bicyclicheterocyclic groups include tetrahydroquinolinyl,tetrahydroisoquinolinyl, tetrahydroindolyl and the like.

Unless stated otherwise, the heteroaryl and heterocyclyl groups groupcan be unsubstituted or substituted with one or more (e.g. up to 5),identical or different, substituents. Examples of substituents for thering carbon and ring nitrogen atoms are: alkyl, alkoxy, halogen,hydroxyl, hydroxyalkyl, fluoroalkyl, aryloxy, amino, cyano, amide,carboxyl, acyl, aryl, heterocyclyl and the like. The substituents can bepresent at one or more positions provided that a stable moleculeresults.

The term “arylalkyl” is meant to include those radicals in which an arylgroup is attached to an alkyl group (e.g., benzyl, phenethyl,pyridylmethyl and the like).

The term “halogen” means, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom.

The term “amino” refers to the group —NH₂ which may be optionallysubstituted with alkyl, acyl, cycloalkyl, aryl, or heterocyclyl whereinthe terms alkyl, acyl, cycloalkyl, aryl, or heterocyclyl are as definedherein above.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, as wellas results in a stable compound, which does not readily undergotransformation such as by rearrangement, cyclization, elimination, etc.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydroiodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galacturonic acids and thelike. Certain specific compounds of the present invention contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

The neutral form of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound can differ from thevarious salt forms in certain physical properties, such as solubility inpolar solvents.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms and the unsolvated forms are encompassed within the scopeof the present invention. Certain compounds of the present invention mayexist in multiple crystalline or amorphous forms. In general, allphysical forms are within the scope of the present invention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Embodiments

The present invention provides compounds represented by the generalformula (I):

wherein:

-   -   Ar is a quinoline or isoquinoline moiety which is substituted or        unsubstituted;    -   B is —O—, —S—, or —NH—;    -   R¹ is hydrogen or S(O)₂R⁴;    -   R² is S(O)₂R⁴, C(O)OR⁵, or C(O)(CH₂)_(n)—C(O)OR⁶;    -   R³ is halogen, cyano, C(O)OR⁷ or C(O)NR⁸R⁹;    -   R⁴ is aryl;    -   R⁵ is (C₁-C₆)alkyl or aryl:    -   R⁶ is hydrogen, (C₁-C₄)alkyl, or aryl,    -   R⁷ is hydrogen or (C₁-C₄)alkyl;    -   R⁸ and R⁹ are independently hydrogen or (C₁-C₆)alkyl; and    -   n is an integer from 1-3; and        their pharmaceutically acceptable salts and solvates.

In certain embodiments, the present invention provides compounds offormula (I),

wherein:

-   -   Ar is a quinoline or isoquinoline moiety which is substituted or        unsubstituted;    -   B is —O—;    -   R¹ and R² are independently H or S(O)₂R⁴;    -   R³ is halogen, preferably chlorine; and    -   R⁴ is substituted or unsubstituted phenyl; such as phenyl        substituted with alkoxy, halogen, cyano, carboxylic acid,        acetamido, substituted alkyl, or unsubstituted alkyl; such as:        -   methyl or substituted-methyl substituted phenyl (e.g.,            2-methylphenyl, 3-methylphenyl, 4-methylphenyl,            3,5-dimethylphenyl, 2,4,6-trimethylphenyl,            2-chloro-4-trifluoromethylphenyl, 3-fluoro-4-methylphenyl or            3-chloro-4-methylphenyl);        -   mono or di-methoxy substituted phenyl (e.g.,            2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl,            2,5-dimethoxyphenyl, 4-methoxyphenyl, or            4-trifluoromethoxyphenyl);        -   halogen substituted phenyl, such as fluoro substituted            phenyl (e.g., 4-fluorophenyl, 2,4-difluorophenyl,            2,6-difluorophenyl, 3,4-difluorophenyl            3-trifluoromethylphenyl, 4-trifluoromethylphenyl, or            2-fluoro-4-chlorophenyl), chloro substituted phenyl (e.g.,            4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl,            3,5-dichlorophenyl, 2 fluoro-4-chlorophenyl,            2-chloro-4-trifluoromethylphenyl, 3-chloro-4-methylphenyl),            or chloro and fluoro substituted phenyl (e.g.,            2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl); or        -   4-cyanophenyl; phenyl-3-carboxylic acid [phenyl-3-COOH]; or            4-acetamidophenyl [CH₃CONH-phenyl]; and            their pharmaceutically acceptable salts and solvates.

In an embodiment, the present invention provides compounds of formula(I),

wherein:

-   -   Ar is isoquinolin-3-yl;    -   B is —O—;    -   R¹ is H;    -   R² is —S(O)₂R⁴;    -   R³ is halogen, preferably chlorine; and    -   R⁴ is substituted or unsubstituted phenyl; such as phenyl        substituted with alkoxy, halogen, or unsubstituted alkyl; such        as:        -   methyl substituted phenyl (e.g., 2-methylphenyl,            3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl,            2,4,6-trimethylphenyl, 3-chloro-4-methylphenyl);        -   mono- or di-methoxy substituted phenyl (e.g.,            4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl,            3,4-dimethoxyphenyl or, 4-trifluoro methoxyphenyl);        -   halogen substituted phenyl, such as fluoro substituted            phenyl (e.g., 4-fluorophenyl, 2,4-difluorophenyl), chloro            substituted phenyl (e.g., 2-chloro-4-fluorophenyl,            2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,            4-chlorophenyl, 2-chloro-4-trifluoromethylphenyl); chloro            and fluoro substituted phenyl (e.g.,            2-fluoro-4-chlorophenyl); or fluoroalkyl substituted phenyl            (e.g., 3-trifluoromethylphenyl, 4-trifluoromethylphenyl); or        -   4-cyanophenyl, phenyl 3-carboxylic acid [phenyl-3-COOH], or            4-acetamidophenyl [CH₃CONH-phenyl]; and            their pharmaceutically acceptable salts and solvates.

In an embodiment, the present invention provides compounds of formula(I),

wherein:

-   -   Ar is quinolin-3-yl;    -   B is —O—;    -   R¹ is H;    -   R² is —S(O)₂R⁴;    -   R³ is halogen, preferably chlorine; and    -   R⁴ is substituted or unsubstituted phenyl; such as phenyl        substituted with alkoxy, halogen, or unsubstituted alkyl; such        as:        -   methyl substituted phenyl (e.g., 4-methylphenyl,            3,5-dimethylphenyl, 2,4,6-trimethylphenyl, or            3-fluoro-4-methylphenyl);        -   mono or di-methoxy substituted phenyl (e.g.,            2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxyphenyl,            4-trifluoromethoxyphenyl);        -   halogen substituted phenyl, such as fluoro substituted            phenyl (e.g., 4-fluorophenyl, 2,4-difluorophenyl,            2,6-difluorophenyl, 3,4-difluorophenyl), chloro substituted            phenyl (e.g., 4-chlorophenyl, 2,4-dichlorophenyl,            3,4-dichlorophenyl, 3,5-dichlorophenyl, or            2-chloro-4-trifluoromethylphenyl), or chloro and fluoro            substituted phenyl (e.g., 2-fluoro-4-chlorophenyl); and            their pharmaceutically acceptable salts and solvates.

In an embodiment, the present invention provides compounds of formula(I),

wherein:

-   -   Ar is quinolin-6-yl;    -   B is —O—;    -   R¹ is H:    -   R² is —S(O)₂R⁴;    -   R³ is halogen, preferably chlorine; and    -   R⁴ is substituted or unsubstituted phenyl; such as phenyl        substituted with alkoxy, halogen, or unsubstituted alkyl; such        as:        -   mono or di-methoxy substituted phenyl (e.g.,            3,4-dimethoxyphenyl);        -   halogen substituted phenyl, such as fluoro substituted            phenyl (e.g., 2,4-difluorophenyl), or chloro substituted            phenyl (e.g., 2,4-dichlorophenyl); and            their pharmaceutically acceptable salts and solvates.

In an embodiment, the present invention provides compounds of formula(I),

wherein:

-   -   Ar is a quinoline or isoquinoline moiety which is substituted or        unsubstituted;    -   B is —O—, —S—, or —NH—;    -   R¹ is S(O)₂R⁴;    -   R² is S(O)R⁴;    -   R³ is halogen; and    -   R⁴ is substituted aryl; and        their pharmaceutically acceptable salts and solvates.

In an embodiment, the present invention provides compound of formula(I), wherein:

-   -   Ar is quinolin-3-yl;    -   B is —O—;    -   R¹ is S(O)₂R⁴;    -   R² is S(O)₂R⁴;    -   R³ is chlorine; and    -   R⁴ is 2,4-dichlorophenyl; and        a pharmaceutically acceptable salt and solvate.

In an embodiment, the present invention provides compounds of formula(I),

wherein:

-   -   Ar is a quinoline or isoquinoline moiety which is substituted or        unsubstituted;    -   B is —O—, —S—, or —NH—;    -   R¹ is 1;    -   R² is C(O)OR;    -   R³ is halogen; and    -   R⁵ is (C₁-C₆)alkyl or aryl; and        their pharmaceutically acceptable salts and solvates.

In an embodiment, the present invention provides compound of formula(I), wherein:

-   -   Ar is quinolin-3-yl;    -   B is —O—;    -   R¹ is H;    -   R² is C(O)OR⁵;    -   R³ is chlorine; and    -   R⁵ is phenyl; and        a pharmaceutically acceptable salt and solvate.

In an embodiment, the present invention provides compounds of formula(I),

wherein:

-   -   Ar is a quinoline or isoquinoline moiety which is substituted or        unsubstituted;    -   B is —O—, —S—, or —NH—;    -   R¹ is H;    -   R² is C(O)(CH₂)_(n)—C(O)OR⁶;    -   R³ is halogen;    -   R⁶ is hydrogen, (C₁-C₄)allyl, or aryl; and    -   n is an integer from 1-3; and        their pharmaceutically acceptable salts and solvates.

In an embodiment, the present invention provides compound of formula(I), wherein:

-   -   Ar is quinolin-3-yl;    -   B is —O—;    -   R¹ is H;    -   R² is C(O)(CH₂)₂—C(O)OR⁶;    -   R³ is chlorine; and    -   R⁶ is hydrogen; and        a pharmaceutically acceptable salt and solvate.

Compounds of the present invention are selected from but not limited to:

-   2,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   3-(N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)sulfamoyl)benzoic    acid,-   3-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4,6-trimethyl    benzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-cyanobenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3,5-dimethylbenzenesulfonamide,-   3,5-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2-methylbenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3-methylbenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide,-   N-(5-Chloro-6-(isoquino-3-yloxy)pyridin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide,-   4-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   4-Chloro-N-(5-chloro-6-isoquinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide,-   2-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-4)-4-methylbenzenesulfonamide,-   3,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,5-dimethoxybenzenesulfonamide,-   2-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4(trifluoromethyl)benzene    sulfonamide,-   N-(4-(N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)sulfamoyl)phenyl)acetamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide,-   2,4-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide,-   3,4-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-(Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide,-   2-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl)benzene-sulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide,-   4-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro    6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-difluorobenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,6-difluorobenzenesulfonamide,-   3,5-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3-fluoro-4-methylbenzenesulfonamide,-   N-(5-(Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,5-dimethylbenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4,6-trimethylbenzenesulfonamide,-   4-chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide,-   N-(5-Chloro-6-(quinolin 3-yloxy)pyridin-3-yl)benzene sulfonamide,-   2,4-Dichloro-N-(5-chloro-6-(quinolin-6-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide,-   2,4-Dichloro-N-[(2,4-dichlorophenyl)sulfonyl]-N-1-chloro-6-(quinolin-3-yloxy)pyridin-3-yl]-benzenesulfonamide,-   2,4-Dichloro-N-(5-chloro-6-(quinolin-6-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide,-   Phenyl 5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylcarbamate, or-   4-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylamino)-4-oxobutanoic    acid; and

their pharmaceutically acceptable salts and solvates.

Suitable compounds of the present invention are selected from but notlimited to:

-   2,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   2-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzene    sulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide,-   3,4-Dichloro-N-(5-chloro-6-(isoquinolin    3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,    or-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide,    and

their pharmaceutically acceptable salts and solvates.

As used herein, the terms “treat” and “therapy” and the like refer toalleviate, slow the progression, prophylaxis, attenuation or cure ofexisting disease (e.g., type 2 diabetes or dyslipidemia).

The term “therapeutically effective amount” is used herein is meant todescribe an amount of a compound of the present invention effective inproducing the desired therapeutic response in a particular patientsuffering from metabolic disorders related to insulin resistance orhyperglycemia.

According to another aspect of present invention there are providedmethods for manufacture of medicaments including compounds of generalformula (I), which are useful for the treatment of metabolic disordersrelated to insulin resistance or hyperglycemia.

According to another aspect of present invention there are providedmethods for the manufacture of a medicament including compounds ofgeneral formula (I), which are useful for the treatment of metabolicdisorders related to insulin resistance or hyperglycemia in a mammal,which medicament is manufactured to be administered, either sequentiallyor simultaneously, with at least one other pharmaceutically activecompound.

While it is possible that compounds of the present invention may betherapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.Accordingly, the present invention further provides for a pharmaceuticalformulation including a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate or a prodrug thereof, for example, togetherwith one or more pharmaceutically acceptable carriers thereof and,optionally, other therapeutic and/or prophylactic ingredients.

The pharmaceutical composition may be in the forms normally employed,such as tablets, lozenges, capsules, powders, syrups, solutions,suspensions and the like specially formulated for oral, buccal,parenteral, transdermal, inhalation, intranasal, transmucosal, implant,or rectal administration, however oral administration is preferred. Forbuccal administration, the formulation may take the form of tablets orlozenges formulated in conventional manner. Tablets and capsules fororal administration may contain conventional excipients such as bindingagents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth,mucilage of starch or polyvinylpyrrolidone), fillers (for example,lactose, sugar, microcrystalline cellulose, maize-starch, calciumphosphate or sorbitol), lubricants (for example, magnesium stearate,stearic acid, talc, polyethylene glycol or silica), disintegrants (forexample, potato starch or sodium starch glycolate) or wetting agents,such as sodium lauryl sulfate. The tablets may be coated according tomethods well known in the art.

Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides. Additionally, formulations of thepresent invention may be formulated for parenteral administration byinjection or continuous infusion. Formulations for injection may takesuch forms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle (e.g., sterile, pyrogen-free water) before use.

The formulations according to the invention may also be formulated as adepot preparation. Such long acting formulations may be administered byimplantation (for example, subcutaneously or intramuscularly) or byintramuscular injection. Accordingly the compounds of the invention maybe formulated with suitable polymeric or hydrophobic materials (as anemulsion in an acceptable oil, for example), ion exchange resins or assparingly soluble derivatives as a sparingly soluble salt, for example.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished diseases or symptoms. Moreover, it will be appreciated thatthe amount of a compound of the invention required for use in treatmentwill vary with the nature of the condition being treated and the age andthe condition of the patient and will be ultimately at the discretion ofthe attendant physician or veterinarian. In general, however, dosesemployed for adult human treatment will typically be in the range of0.02-5000 mg per day or 1-1500 mg per day. The desired dose mayconveniently be presented in a single dose or as divided dosesadministered at appropriate intervals, for example as two, three, fouror more sub-doses per day.

The formulations according to the invention may contain between 0.1-99%of the active ingredient, conveniently from 30-95% for tablets andcapsules and 3-50% for liquid preparations.

Furthermore, in addition to at least one compound of the general formula(I), as active ingredient, the pharmaceutical compositions may alsocontain one or more other therapeutically active ingredients.

According to an embodiment of the present invention there is provided amethod for the treatment of metabolic disorders related to insulinresistance or hyperglycemia, including administering to a mammal in needthereof a therapeutically effective amount of a compound of formula (I).

According to an embodiment of the present invention there is provided amethod for the treatment of metabolic disorders related to insulinresistance or hyperglycemia, including type 2 diabetes, obesity, glucoseintolerance, dyslipidemia, hyperinsulinemia, atherosclerotic disease,polycystic ovary syndrome, coronary artery disease, hypertension, aging,non alcoholic fatty liver disease, infections, cancer and stroke,including administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of formula (I).

According to an embodiment of the present invention there is provided amethod for the treatment of type 2 diabetes and disorders relatedthereto, including administering to a mammal in need thereof atherapeutically effective amount of a compound of formula (I).

According to an embodiment of the present invention there is provided amethod for the treatment of dyslipidemia and disorders related thereto,including administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of formula (I).

According to an embodiment the compounds of present invention are usefulfor the treatment of metabolic disorders related to insulin resistanceor hyperglycemia.

According to an embodiment the compounds of present invention are usefulfor the treatment of metabolic disorders related to insulin resistanceor hyperglycemia, including type 2 diabetes, glucose intolerance,dyslipidemia, hyperinsulinemia, atherosclerotic disease, polycysticovary syndrome, coronary artery disease, hypertension, aging, nonalcoholic fatty liver disease, infections, cancer and stroke.

According to an embodiment the compounds of present invention are usefulfor the treatment of type 2 diabetes.

According to an embodiment the compounds of present invention are usefulfor the treatment of dyslipidemia.

Representative compounds useful in the treatment of metabolic disordersrelated to insulin resistance or hyperglycemia, in accordance with thepresent invention are selected from but are not limited to thefollowing:

-   2,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin    3-yl)benzenesulfonamide,-   3-(N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)sulfamoyl)benzoic    acid,-   3-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4,6-trimethyl    benzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-cyanobenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3,5-dimethylbenzenesulfonamide,-   3,5-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2-methylbenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3-methylbenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide,-   4-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   4-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide,-   N-(5-Chloro-6    (isoquinolin-3-yloxy)pyridin-1-yl)-2,4-difluorobenzenesulfonamide,-   2-Chloro-N-(5-chloro-6-(isoquinolin-3    yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide,-   3,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide,-   N-(5-(Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,5-dimethoxybenzenesulfonamide,-   2-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4(trifluoromethyl)benzene    sulfonamide,-   N-(4-(N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)sulfamoyl)phenyl)acetamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide,-   2,4-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide,-   3,4-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide,-   2-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide,-   4-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-difluorobenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,6-difluorobenzenesulfonamide,-   3,5-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3-fluoro-4-methylbenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,5-dimethylbenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4,6-trimethylbenzenesulfonamide,-   4-chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   2,4-Dichloro-N-(5-chloro-6-(quinolin    6-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide,-   2,4-Dichloro-N-[(2,4-dichlorophenyl)sulfonyl]-N-[5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl]-benzenesulfonamide:-   2,4-Dichloro-N-(5-chloro-6-(quinolin-6-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-quinolin-6-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide,-   Phenyl 5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylcarbamate,-   4-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylamino)-4-oxobutanoic    acid, and

their pharmaceutically acceptable salts and solvates.

Suitable compounds useful in the treatment of metabolic disordersrelated to insulin resistance or hyperglycemia, in accordance with thepresent invention are selected from but are not limited to thefollowing:

-   2,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   2-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide,-   N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-v)-4-methylbenzenesulfonamide,-   3,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide,-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide,    or-   N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide,    and

their pharmaceutically acceptable salts and solvates.

Preparation of the Compounds

According to a further aspect of the invention, there is provided aprocess for the preparation of compounds, of the general formula (I),

wherein:

-   -   Ar is a quinoline or isoquinoline moiety which is substituted or        unsubstituted;    -   B is —O—, —S—, or —NH—;    -   R¹ is hydrogen or S(O)₂R⁴;    -   R² is S(O)₂R⁴, C(O)OR⁵, or C(O)(CH₂)_(n)—C(O)OR⁶;    -   R³ is halogen, cyano, C(O)OR⁷, or C(O)NR⁸R⁹;    -   R⁴ is aryl;    -   R⁵ is (C₁-C₆)alkyl or aryl;    -   R⁶ is hydrogen, (C₁-C₄)alkyl, or aryl;    -   R⁷ is hydrogen or (C₁-C₄)alkyl;    -   R⁸ and R⁹ are independently hydrogen or (C₁-C₆)alkyl; and    -   n is an integer from 1-3; and        their pharmaceutically acceptable salts and solvates.

The compounds of general formula (I), according to the invention can beprepared by, or in analogy with, standard synthetic methods, andespecially according to, or in analogy with, Scheme 1.

As shown in scheme 1, compounds of the present invention can be preparedby reacting compound of formula (II) wherein R³ is as defined above andHal is selected from fluorine, chlorine, bromine or iodine with acompound of formula (III) wherein Ar and B are as defined above, in thepresence of a solvent such as dimethyl formamide, dimethyl sulfoxide,tetrahydrofuran, dioxane, or acetronitrile, optionally in the presenceof a base such as cesium carbonate, potassium carbonate, sodiumcarbonate, sodium hydroxide, potassium hydroxide, or potassium fluorideto provide the compound of formula (IV) wherein Ar, B and R³ are asdefined above. The nitro group of compound of formula (IV) is reduced tothe corresponding amino group to obtain compound of formula (V) whereinAr, B and R³ are as defined above. Reduction of the nitro group ma becarried out by using SnCl₂, in a solvent such as ethyl acetate; or byusing Fe/HCl; or in presence of gaseous hydrogen and a catalyst such asPd—C, Rh—C, Pt—C; or any suitable method known in the art.

The compound of formula (V) is further converted to the desired compoundof formula (I) wherein R¹ is H, R² is —SO₂R⁴ and Ar, B, R³ and R⁴ are asdefined above, by reacting with one equivalent of Hal-SO₂R⁴ wherein Halis represented by fluorine, chlorine, bromine, or iodine and R⁴ is asdefined above, in the presence of pyridine or triethyl amine as a baseand a solvent selected from acetonitrile, dichloromethane, chloroform,carbon tetrachloride, tetrahydrofuran, or dioxane.

The compound of formula (V) is converted to the desired compound offormula (I) wherein R¹ and R² are —SO₂R⁴ and Ar, B, R³ and R⁴ are asdefined above, by reacting with two equivalents of Hal-SO₂R⁴ wherein Halis represented by fluorine, chlorine, bromine, or iodine and R⁴ is asdefined above, at 45° C., in the presence of triethyl amine as a baseand a solvent selected from acetonitrile, dichloromethane, chloroform,carbon tetrachloride, tetrahydrofuran, or dioxane.

The compound of formula (V) may also be converted to the desiredcompound of formula (I) wherein R¹ is H, R² is C(O)(CH₂)_(n)—C(O)OH andAr, B, n and are as defined above, by refluxing with an anhydride[(CH₂)_(n)(CO)₂O], in the presence a solvent selected from benzene,toluene, tetrahydrofuran, dioxane. The acid of formula (I) may beconverted to the ester wherein R² is C(O)(CH₂)_(n)—C(O)OR⁶ and Ar, B, n,R¹, and R³ are as defined above and R⁶ is (C₁-C₄)alkyl or aryl, bystandard esterification reactions known in the literature.

The compound of formula (V) may also be converted to the desiredcompound of formula (I) wherein R¹ is H, R² is C(O)OR⁵ and Ar, B, R³,and R⁵ are as defined above, by refluxing with R⁵-carbonochloridate, inthe presence of pyridine or triethyl amine as a base and a solventselected from acetonitrile, dichloromethane, chloroform, carbontetrachloride, tetrahydrofuran, or dioxane.

The compounds of general formula (I), wherein Ar, B, R¹, R² and R³ areas defined above may be converted into pharmaceutically acceptable saltsby standard procedures known in the literature.

The compounds of this invention can be prepared as illustrated by theaccompanying working examples. The following examples are set forth toillustrate the synthesis of some particular compounds of the presentinvention and to exemplify general processes. Accordingly, the followingExamples section is in no way intended to limit the scope of theinvention contemplated herein.

EXPERIMENTAL List of Abbreviations

HCl: Hydrochloric acid;POCl₃: Phosphorous oxychloride;Cs₂CO₃: Cesium carbonate

DCM: Dichloromethane DMF: Dimethylformamide

DMSO: Dimethyl sulfoxideCPM: Counts per minute

mpk: mg per Kg. od: Once a day bid: Twice a day

HEPES: N-(2-hydroxyethyl)-piperazine-N′-2-ethanesulfonic acidMP (DSC): melting point (Differential Scanning Calorimetry)CMC: Carboxy methyl cellulose

Preparation 1: 5-Chloro-6-(quinolin-3-yloxy)pyridin-3-amine Step i.2-Hydroxy-3-chloro-5-nitro pyridine

2-Hydroxy-5-nitro pyridine (1 g, 7.14 mmol) was added portion wise to4.5 mL of concentrated HCl under constant stirring and then heated to50° C. To this was added a solution of sodium chlorate (266 mg, 2.5mmol) in water (4 mL). The reaction was maintained at the sametemperature for an additional hour, and then cooled to 0° C. Theprecipitate obtained was filtered, washed with water and dried to obtain2-hydroxy-3-chloro-5-nitro pyridine.

Yield: 850 mg (68.2%); m.p.: 195-197° C.; ¹H NMR (DMSO-d₆) δ: 8.36 (d,1H, J=2.5 Hz), 8.65 (d, 1H, J=2.5 Hz).

Step ii. 2,3-Dichloro-5-nitro pyridine

Quinoline (0.3 mL, 2.34 mmol) was added to POCl₃ (0.5 ml. 4.68 mmol) at(0° C. under nitrogen. To this stirred mixture was added2-hydroxy-3-chloro-5-nitro pyridine (816 mg, 4.68 mmol) (productobtained in step i) The reaction mixture was heated at 120° C. for 2hours, cooled to 0° C. followed by addition of ice cold water. Theprecipitate obtained was filtered, washed with water and dried to obtain2,3-dichloro-5-nitro pyridine.

Yield: 630 mg (70.3%); m.p.: 53° C.; ¹H NMR (DMSO-d₆) δ: 8.94 (d, 1H,J=2.5 Hz), 9.16 (d, 1H, J=2.5 Hz).

Step iii. 3-(3-Chloro-5-nitro-pyridin-2-yloxy)-quinoline

Dry dimethylformamide (10 mL) was added to 3-hydroxy quinoline (459 mg,3.16 mmol) under stirring. To the stirred solution was added Cs₂CO₃(1.03 g, 3.16 mmol) at room temperature. After 30 minutes2,3-dichloro-5-nitro pyridine (610 mg, 3.16 mmol) obtained in, step ii,was added and the stirring was continued further for 18 hours. Thesolvent was removed under vacuum and to the resulting mass was addedwater (20 mL), extracted with ethyl acetate, dried over sodium sulfateand concentrated under vacuum to obtain crude3-(3-chloro-5-nitro-pyridin-2-yloxy)-quinoline that was purified bycolumn chromatography (silica gel, gradient 10-30% ethyl acetate in perether to obtain the title compound.

Yield: 911 mg (96%); m.p.: 123-127° C.; ¹H NMR (DMSO-d₆) δ: 7.69 (t, 1H,j=6.99), 7.82 (t, 1H, J=6.89), 7.98 (d, 1H, J=8.09 Hz), 8.09 (d, 1H,J=8.39 Hz), 8.35 (d, 1H, J=2.8 Hz), 8.95 (d, 1H, 2.51 Hz), 9.03 (d, 2H,J=2.5 Hz); MS: 302 (M+1).

Step iv. 5-Chloro-6-(quinolin-3-yloxy)pyridin-3-amine

To a solution of 3-Chloro-2-quinoloxy-5-nitropyridine (2.51 g, 8.34mmol) (obtained in step iii), in ethyl acetate (50 mL) was addedstannous chloride dihydrate (7.52 g, 33.36 mmol) at room temperature.Stirring was continued further for 18 hours. Removed the solvent undervacuum and chloroform (50 min) was added. To the stirred mixture wasadded 1N sodium hydroxide solution until a clear solution was obtained.Separated the organic layer and extracted with chloroform. Thechloroform layer was washed with brine and water successively, driedover sodium sulfate and concentrated under vacuum. The crude product waspurified by column chromatography (silica gel, gradient 30-50% ethylacetate in pet ether) to obtain the title compound.

Yield: 1.85 g (81.5%); m.p.: 156-159° C.; ¹H NMR (DMSO-d₆), δ: 5.49 (s,2H), 7.26 (d, 1H, J=2.56 Hz), 7.49 (d, 1H, J=2.57 Hz), 7.60 (td, 1H,J=8.07 and 1.19 Hz), 7.70 (td, 1H, J=6.9 and 1.46 Hz), 7.85 (d, 1H,J=2.7 Hz), 7.92 (dd, 1H, J=7.4 and 1.0 Hz), 8.01 (d, 1H, J=2.7 Hz), 8.75(d, 1H, J=2.7 Hz); MS: 272 (M+1).

Preparation 2: 5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine

Isoquinolin-3-ol was reacted with 2,3-dichloro-5-nitro pyridine toobtain 3-(3-chloro-5-nitropyridin-2-yloxy)isoquinoline which was furtherconverted to 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine as per theprocedure described in preparation 1, step iii and iv

¹H NMR (CDCl₃) δ: 5.49 (s, 2H), 7.21 (d, J=2.4 Hz, 1H), 7.32 (s, 1H),7.51 (t, J=7.2 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.70 (t, J=7.2 Hz, 1H),7.90 (d, J=8.1 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 9.00 (s, 1H); MS (ES):272 (M+1).

Preparation 3: 5-Chloro-6-(quinolin-6-yloxy)pyridin-3-amine

Quinolin-6-ol was reacted with 2,3-dichloro-5-nitro pyridine to obtain6-(3-chloro-5-nitropyridin-2-yloxy)quinoline which was further convertedto 5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine as per the proceduredescribed in preparation 1 step iii and iv.

¹H NMR (DMSO-d₆) δ: 5.53 (s, 2H), 7.27 (brs, 1H), 7.37 (brs, 1H),7.48-7.56 (m, 3H), 8.02 (d, 1H), 8.27 (d, 1H), 8.81 (d, 1H); MS (KS):272.05 (M+1).

General Procedure for Preparation of Quinoline and IsoquinolineCompounds

To a stirred solution of amine (as obtained in preparation 1, 2 or 3) (1mmol) in DCM, pyridine (1-5 mmol) was added which was followed byaddition of substituted benzenesulfonylchloride (1 mmol). The reactionmixture was stirred at room temperature (25° C.). Reaction mixture wasdiluted using DCM, washed with water, dried over anhydrous sodiumsulfate and concentrated. The crude product was purified using columnchromatography (silica gel) to obtain the desired compound.

The compounds of example 1-44 and 46-48 were prepared by this procedure.

General Procedure for Salt Formation

Procedure A:

Compound of formula (I) was dissolved in 1:1 ethyl acetate and DCM soent mixture. To the clear solution 1 equivalent of corresponding acid(such as toluene sulfonic acid, methane sulfonic acid, or benzenesulfonic acid) was added and stirred for 30-45 mins at room temperature(25° C.). The salt was filtered off and characterized by ¹H NMR and MP(DSC).

Procedure B:

Compound of formula (I) was dissolved in ethanol (a large excess andheating was required to obtained a clear solution). To the clearsolution, 1 equivalent of the corresponding acid (such as toluenesulfonic acid, methane sulfonic acid, or benzene sulfonic acid) wasadded. After refluxing for 3 hours; the solvent was removed and the saltobtained was characterized by ¹H NMR and MP (DSC).

Example 12,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per theprocedure described in preparation 2) and 2,4-dichlorobenzenesulfonylchloride.

m.p.: 203° C.-205° C.; ¹H NMR (DMSO-d₆) δ: 7.50-7.57 (m, 3H), 7.67-7.71(m, 2H), 7.77 (d, 1H), 7.84-7.87 (m, 2H), 7.97 (d, 1H), 8.04 (d, 1H),8.98 (s, 1H), 11.06 (s, 1H); MS (ES): 479.9 (M−1).

Mesylate Salt

m.p.: 211° C.-213° C.; ¹H NMR (DMSO-d₆) δ: 2.33 (s, 3H), 7.64-7.56 (m,3H), 7.78-7.73 (m, 2H), 7.85 (d, 1H), 7.94-7.90 (m, 2H), 8.05 (d, 1H),8.11 (d, 1H), 9.05 (s, 1H), 11.10 (s, 1H).

Sodium Salt

The compound of example 1 (250 mg, 0.522 mmol) was dissolved in excessamount (40-50 mL of methanol and the reaction mixture was warmed at 60°C. to get a clear solution. To the stirred solution, 1.0 equivalent ofsodium hydroxide was added as a solution in methanol. The solution wasrefluxed for 2-3 hours. After completion of the reaction, the solventwas removed and dried.

m.p.: 291° C.-293° C.; —NMR (DMSO-d₆) δ: 7.52 (s, 1H), 7.60-7.57 (dd,2H), 7.68 (d, 1H), 7.74 (t, 1H), 7.79 (d, 1H), 7.85 (d, 1H), 7.93 (d,1H), 8.03 (d, 1H), 8.10 (d, 1H), 9.04 (s, 1H), 11.10 (s, 1H).

Example 23-(N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)sulfamoyl)benzoicacid

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 3-(chlorosulfonyl)benzoicacid.

¹H NMR (DMSO-d₆) δ: 7.56-7.62 (m, 2H), 7.70-7.79 (m, 4H), 7.91-7.99 (m,2H), 8.10 (d, 1H), 8.27 (d, 1H), 8.48 (s, 1H), 9.06 (s, 1H), 10.78 (s,1H); MS (ES): 456 (M+1), 454 (M−1).

Example 33-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and3-chloro-4-methylbenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 2.38 (s, 3H), 7.56-7.65 (m, 4H), 7.74-7.83 (m, 4H),7.94 (d, 1H), 8.12 (d, 1H), 9.07 (s, 1H), 10.71 (s, 1H); MS (ES): 458.02(M−1).

Example 4N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4,6-trimethylbenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and2,4,6-trimethylbenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 2.24 (s, 3H), 2.50 (s, 3H), 2.54 (s, 3H), 7.05 (s,2H), 7.56-7.62 (m, 2H), 7.68 (d, 1H), 7.74-7.79 (m, 2H), 7.94 (d, 1H),8.12 (d, 1H), 9.06 (s, 1H), 10.77 (s, 1H); MS (ES): 454.08 (M+1).

Example 5N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-cyanobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3 amine (obtained as perprocedure described in preparation 2) and 4-cyanobenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 7.59-7.64 (m, 2H), 7.75-7.82 (m, 2H), 7.94-7.97 (m,3H), 8.08-8.14 (m, 3H), 9.09 (s, 1H), 10.94 (s, 1H); MS (ES): 435.0(M−1).

Example 6N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3,5-dimethylbenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 3,5-dimethylbenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 2.33 (s, 6H), 7.3 (s, 1H), 7.41 (s, 1H), 7.61 (m,2H), 7.77 (m, 3H), 7.94 (d, 1H), 8.12 (d, 1H), 9.07 (s, 1H); MS (ES):440.15 (M−1).

Example 73,5-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide

The tile compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 3,5-dichlorobenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 7.61 (m, 2H), 7.77-7.85 (m, 5H), 7.97 (m, 2H), 8.13(d, 1H), 9.19 (s, 1H), 10.90 (s, 1H); MS (ES): 479.97 (M+1).

Example 8N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2-methylbenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 2-methylbenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 2.62 (s, 3H), 7.38 (m, 2H), 7.54-7.63 (m, 3H), 7.71(d, 1H), 7.76 (t, 1H), 7.84 (d, 1H), 7.88-7.96 (m, 2H), 8.12 (d, 1H),9.06 (s, 1H), 10.82 (s, 1H); MS (ES): 426.11 (M+1).

Example 9N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3-methylbenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 3-methylbenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 2.73 (s, 3H), 7.49 (d, 2H), 7.58-7.63 (m, 4H),7.71-7.82 (m, 3H), 7.95 (d, 1H), 8.12 (d, 1H), 9.37 (s, 1H), 10.62 (s,1H): MS (ES): 426.11 (M+1).

Example 10N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and3-(trifluoromethyl)benzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.57-7.62 (m, 2H), 7.72-7.87 (m, 4H), 7.92 (d, 1H),8.03-8.12 (m, 4H), 9.06 (s, 1H), 10.80 (s, 1H); MS (ES): 480.04 (M+1).

Example 11N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and4-(trifluoromethyl)benzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.57-7.62 (m, 2H), 7.72-7.81 (min, 31-H), 7.91-7.94(m, 1H), 7.98 (m, 4H), 8.11 (d, 1H) 9.06 (s, 1H), 10.90 (s, 1H); MS(ES): 478.0 (M−1).

Example 124-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 4-chlorobenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 7.56-7.62 (m, 2H), 7.63-7.68 (m, 2H), 7.72-7.81 (m,5H), 7.92 (d, 1H), 8.10 (d, 1H), 9.06 (s, 1H), 10.75 (s, 1H); MS (ES):444.0 (M−1).

Example 134-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and4-chloro-2-fluorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.48 (d, 1H), 7.58-7.61 (m, 2H), 7.74-7.77 (m, 3H),7.83-7.87 (m, 2H), 7.93 (d, 1H), 8.11 (d, 1H), 9.06 (s, 1H), 11.08 (s,1H); MS (ES): 462.0 (M−1).

Example 14N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 2,4-difluorobenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 7.28 (dt, 1H), 7.54-7.63 (m, 3H), 7.73-7.79 (m, 2H),7.85 (d, 1H), 7.89-7.97 (m, 2H), 8.12 (d, 1H), 9.07 (s, 1H), 11.03 (s,1H); MS (ES): 448.08 (M+1).

Example 152-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and2-chloro-4-fluorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.41 (dt, 1H), 7.56-7.61 (m, 2H), 7.72-7.77 (m, 3H),7.83 (d, 1H), 7.92 (d, 1H), 8.09-8.14 (m, 2H), 9.05 (s, 1H), 11.08 (s,1H); MS (ES): 461.95 (M−1).

Example 16N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 4-methylbenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 2.33 (s, 3H), 7.35 (d, 2H), 7.54-7.57 (m, 2H),7.59-7.70 (m, 2H), 7.73-7.90 (m, 3H), 7.91 (d, 1H), 8.08 (d, 1H), 9.03(s, 1H), 10.58 (s, 1H); MS (ES): 424.02 (M−1).

Example 173,4-Dichloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 3,4-dichloro-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 7.57-7.62 (m, 2H), 7.79-7.94 (m, 5H), 7.97 (m, 2H),8.10 (d, 1H), 9.07 (s, 1H), 10.80 (s, 1H); MS (ES): 477.92 (M−1).

Example 18N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzene-sulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and4-(trifluoromethoxy)benzene-1-sulfonyl chloride.

¹H NMR (CDCl₃) δ: 7.25-7.32 (m, 2H), 7.47 (s, 3H), 7.54-7.62 (m, 3H),7.72 (t, 1H), 7.80-7.85 (m, 3H), 7.85-8.03 (m, 2H), 9.10 (s, 1H); MS(ES): 493.98 (M−1).

Example 19N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,5-dimethoxybenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and2,5-dimethoxybenzene-1-sulfonylchloride.

¹H NMR (CDCl₃) δ: 3.78 (s, 3H), 3.98 (s, 3H), 6.96 (d, 1H), 7.04-7.08(m, 2H), 7.30 (d, 1H), 7.42 (s, 1H), 7.54 (t, 1H), 7.65-7.70 (m, 2H),7.79-7.81 (m, 2H), 7.96 (d, 1H), 9.01 (s, 1H); MS (ES): 472.11 (M+1).

Example 202-Chloro-N-(5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4(trifluoromethyl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.57-7.62 (m, 2H), 7.73-7.78 (m, 2H), 7.86 (d, 1H),7.96 (d, 2H), 8.12 (d, 1H), 8.16 (s, 1H), 8.25 (d, 1H), 9.05 (s, 1H),11.28 (s, 1H); MS (ES): 511.92 (M−1).

Example 21N-(4-(N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)sulfamoyl)phenyl)acetamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 4-acetamidobenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 2.06 (s, 3H), 7.56-7.62 (m, 2H), 7.68-7.73 (m, 4H),7.76-7.78 (m, 3H), 7.93 (d, 1H), 8.11 (d, 1H), 9.06 (s, 1H), 10.36 (s,1H), 10.54 (s, 1H); MS (ES): 466.98 (M−1).

Example 22N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and3,4-dimethoxybenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 3.35 (s, 3H), 3.79 (s, 3H), 7.08 (d, 2H), 7.59-7.76(m, 5H), 7.94 (d, 1H), 8.03 (d, 1H), 8.15 (s, 1H), 8.78 (d, 1H), 10.45(s, 1H); MS (ES): 469.98 (M−1).

Example 23N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-2,4-dimethoxybenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and2,4-dimethoxybenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 3.81 (s, 3H), 3.85 (s, 3H), 6.59-6.67 (m, 2H),7.54-7.61 (m, 2H), 7.68-7.81 (m, 5H), 7.92 (d, 1H), 8.10 (d, 1H), 9.04(s, 1H); MS (ES): 472.11 (M−1).

Example 24N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 4-methoxybenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 3.81 (s, 3H), 7.10 (d, 2H), 7.59 (m, 2H), 7.73 (m,5H), 7.92 (d, 1H), 8.10 (d, 1H), 9.05 (s, 1H), 10.14 (s, 1H); MS (ES):442.08 (M+1).

Example 25N-(5-Chloro-6-(isoquinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as perprocedure described in preparation 2) and 4-fluorobenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 7.43 (br s, 2H), 7.57 (br s, 2H), 7.83-7.93 (m, 5H),8.11 (m, 2H), 9.06 (s, 1H), 10.75 (s, 1H); MS (ES): 430.08 (M+1).

Example 26N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 4-methoxybenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆): 3.80 (s, 3H), 7.10 (dd, 2H), 7.64 (t, 1H), 7.69 (d,2H), 7.70 (d, 1H), 7.72-7.75 (m, 2H), 7.95 (d, 1H), 8.04 (d, 1H), 8.15(d, 1H), 8.78 (d, 1H), 10.44 (s, 1H); MS (ES): 440.06 (M−1).

Example 272,4-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 2,4-dichlorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.59-7.64 (m, 2H), 7.71-7.76 (m, 3H), 7.90-7.94 (m,2H), 8.00 (d, 1H), 8.03 (d, 1H), 8.15 (d, 1H), 8.77 (d, 1H), 11.05 (s,1H); MS (ES): 479.98 (M+1).

Example 28N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 4-methylbenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 2.3 (s, 3H), 7.35 (d, 2H), 7.59-7.75 (m, 6H), 7.92(d, 1H), 8.01 (d, 1H), 8.15 (s, 1H), 8.77 (d, 1H), 10.52 (s, 1H); MS(ES): 424.09 (M−1), 426.08 (M+1).

Example 293,4-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 3,4-dichlorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.62 (t, 1H), 7.66 (d, 1H), 7.72-7.74 (m, 2H), 7.79(d, 1H), 7.84 (d, 1H), 7.93-7.95 (m, 2H), 8.02 (d, 1H), 8.17 (d, 1H),8.78 (d, 1H), 10.48 (s, 1H); MS (ES): 479.89 (M+1).

Example 30N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 3,4-dimethoxybenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 3.76 (s, 3H), 3.79 (s, 3H), 7.06 (d, 1H), 7.23 (d,1H), 7.30 (d m, 1H), 7.62 (t, 1H),), 7.70-7.75 (m, 3H), 7.92 (d, 1H),8.02 (d, 1H), 8.14 (d, 1H), 8.76 (d, 1H), 10.40 (s, 1H); MS (ES): 469.98(M−1).

Example 31N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-dimethoxybenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 2,4-dimethoxybenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 3.79 (s, 3H), 3.83 (s, 3H), 6.57 (d, 1H), 6.65 (s,1H), 7.58-7.75 (m, 5H), 7.91 (d, 1H), 8.01 (d, 1H), 8.12 (s, 1H), 8.75(d, 1H), 10.23 (s, 1H);MS (ES): 47.02 (M−1).

Example 32N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 4-trifluoromethoxybenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 7.56-7.64 (m, 3H), 7.71-7.79 (m, 2H), 7.86-7.94 (m,3H), 8.01 (d, 1H), 8.16 (s, 1H), 8.78 (s, 1H), 9.06 (s, 1H), 10.74 (s,1H); MS (ES): 493.99 (M−1).

Example 332-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl)benzene-sulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.60 (s, 1H), 7.72-7.77 (m, 3H), 7.90 (s, 2H), 8.00(s, 1H), 8.13-8.20 (m, 3H), 8.75 (s, 1H), 11.21 (s, 1H); MS (ES): 513.99(M+1).

Example 34N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 2,4-difluorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.23-7.29 (dt, 1H), 7.52-7.64 (m, 2H), 7.70-7.78 (m,3H), 7.86-7.94 (m, 2H), 8.01 (d, 1H), 8.16 (d, 1H), 8.77 (d, 1H), 10.99(s, 1H); MS (ES): 445.92 (M−1).

Example 35N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 4-fluorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) a: 7.12 (d, 1H), 7.36 (t, 2H), 7.57-7.62 (m, 2H),7.68-7.78 (m, 3H), 7.91 (d, 1H), 8.01 (d, 1H), 8.08 (s, 1H), 8.71 (s,1H), 10.40 (s, 1H); MS (ES): 429.95 (M+1).

Example 364-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 4-chlorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.58-7.66 (m, 4H), 7.70-7.76 (m, 4H), 7.91 (dd, 1H),8.01 (d, 1H), 8.15 (d, 1H), 8.77 (d, 1H), 10.97 (s, 1H); MS (ES): 446.00(M+1).

Example 37N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-difluorobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 3,4-difluorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.61-7.69 (m, 3H), 7.74-7.78 (m, 2H), 7.80 (d, 1H),7.84 (t, 1H), 7.94 (d, 1H), 8.04 (d, 1H), 8.19 (d, 1H), 8.80 (d, 1H),10.71 (s, 1H); MS (ES): 448.03 (M+1).

Example 38N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,6-difluorobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 2,6-difluorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.29 (t, 2H), 7.60 (dt, 1H), 7.70-7.75 (m, 2H), 7.81(d, 1H), 7.84 (d, 1H), 7.94 (d, 1H), 8.03 (d, 1H), 8.18 (d, 1H), 8.92(d, 1H), 11.27 (s, 1H); MS (ES): 448.03 (M+1).

Example 393,5-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 3,5-dichlorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.64 (d, 1H), 7.74-7.78 (m, 3H), 7.82 (d, 1H), 7.94(d, 2H), 8.01 (s, 1H), 8.04 (d, 1H), 8.19 (d, 1H), 8.80 (d, 1H), 10.79(s, 1H); MS (ES): 479.94 (M+1).

Example 40N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3-fluoro-4-methylbenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 3-fluoro-4-methylbenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 2.28 (s, 3H), 7.48-7.54 (m, 3H), 7.64 (d, 1H), 7.72(d, 1H), 7.75 (d, 1H), 7.78 (d, 1H), 7.94 (d, 1H), 8.04 (d, 1H), 8.18(d, 1H), 8.79 (d, 1H), 10.65 (s, 1H); MS (ES): 444.04 (M+1).

Example 41N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,5-dimethylbenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 3,5-dimethylbenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 2.31 (s, 6H), 7.29 (s, 1H), 7.39 (s, 2H), 7.61 (t,1H), 7.71-7.78 (m, 3H), 7.94 (d, 1H), 8.04 (d, 1H), 8.17 (d, 1H), 8.79(d, 1H), 10.51 (s, 1H); MS (ES): 440.06 (M+1).

Example 42N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4,6-trimethylbenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 2,4,6-trimethylbenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 2.31 (s, 3H), 2.50 (s, 6H), 7.04 (s, 2H), 7.62-7.66(m, 3H), 7.71 (dt, 1H), 7.92 (d, 1H), 8.03 (d, 1H), 8.14 (d, 1H), 8.77(d, 1H), 10.52 (s, 1H); MS (ES): 454.09 (M+1).

Example 434-chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and 4-chloro-2-fluorobenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) δ: 7.44 (dd, 1H), 7.58 (dt, 1H), 7.70-7.80 (m, 5H),7.86 (d, 1H), 8.01 (d, 1H), 8.15 (d, 1H), 8.77 (d, 1H), 11.03 (s, 1H);MS (ES): 464 (M+1).

Example 44N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) and benzenesulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.57-7.76 (m, 9H), 7.92 (d, 1H), 8.01 (d, 1H), 8.15(s, 1H), 8.77 (s, 1H), 10.59 (s, 1H); MS (ES): 411.99 (M+1).

Example 452,4-Dichloro-N-[(2,4-dichlorophenyl)sulfonyl]-N-[5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl]-benzenesulfonamide

Dry dichloromethane (15 mL) was added to 5-Chloro-6-(quinolin-3yloxy)-pyridin-3-yl amine (250 mg, 1 mmol) obtained in preparation 1. Tothe stirred solution was added 2,4-dichlorobenzenesulfonyl chloride (492mg, 2.2 mmol) followed by the addition of triethylamine (2.2 mmol). Thereaction mixture was then maintained at 45° C. for 15 hours, cooled toroom temperature (25° C.) and diluted with dichloromethane. Thedichloromethane layer was washed with water, dried over sodium sulfateand concentrated under vacuum to get the crude, which was furtherpurified by column chromatography (silica gel).

Yield: 483 mg (76%); ¹H NMR (CDCl₃) δ: 7.47 (dd, 2H); 7.54 (d, 2H); 7.59(td, 1H); 7.72 (ddd, 1H); 7.84 (d, 1H); 7.86 (d, 1H); 7.90 (d, 1H); 8.00(d, 1H); 8.14 (m, 3H), 8.82 (d, 1H).

Example 462,4-Dichloro-N-(5-chloro-6-(quinolin-6-yloxy)pyridin-3-yl)benzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 3) and 2,4-dichlorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 7.55-7.70 (m, 3H), 7.77-7.92 (m, 4H), 8.03-8.06 (m,2H), 8.31 (m, 1H), 8.88 (m, 1H), 11.15 (m, 1H); MS (ES): 479.9 (M+1).

Example 47N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 3) and 3,4-dimethoxybenzene-1-sulfonylchloride.

¹H NMR (DMSO-d₆) a: 3.78 (s, 3H), 3.80 (s, 3H), 7.07-7.17 (m, 1H), 7.34(s, 2H), 7.83-7.96 (m, 5H), 8.31 (d, 1H), 8.8.3 (d, 1H), 9.15 (d, 1H),10.70 (s, 1H); MS (ES): 472.07 (M+1)

Example 48N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

The title compound was prepared by reacting5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 3) and 2,4-difluorobenzene-1-sulfonyl chloride.

¹H NMR (DMSO-d₆) δ: 6.97-7.17 (m, 1H), 7.27-7.55 (m, 1H), 7.66-7.74 (m,1H), 7.86-7.99 (m, 3H), 8.08 (t, 1H), 8.36 (m, 1H), 8.63 (t, 1H), 8.88(d, 1H), 8.94 (d, 1H), 11.20 (brs, 1H); MS (ES): 448.04 (M+1).

Example 49 Phenyl 5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylcarbamate

The title compound was obtained by reacting5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per proceduredescribed in preparation 1) with phenyl carbonochloridate.

¹H NMR: (DMSO-d₆) δ: 10.59 (s, 1H), 8.82 (d, 1H), 8.21 (d, 1H), 8.16 (d,2H), 8.04 (d, 1H), 7.95 (d, 1H), 7.73 (dt, 1H), 7.61 (t, 1H), 7.42 (t,2H), 7.26 (d, 1H), 7.23 (d, 2H).

Example 504-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylamino)-4-oxobutanoic acid

5-Chloro-6(quinolin-3-yloxy)-pyridin-3-yl amine (1 mmol) (obtained asper procedure described in preparation 1) was dissolved in toluene underheating. To the clear solution was added succinic anhydride (1 mmol) andrefluxed at 120° C. for 6 hours. The solvent the evaporated and thecrude obtained was purified by column chromatography to provide thetitle compound.

¹H NMR: (DMSO-d₆) δ: 12.14 (brs, 1H), 10.36 (s, 1H), 8.80 (s, 1H), 8.39(s, 1H), 8.02 (m, 4H), 7.64 (d, 2H), 2.48 (m, 4H).

Pharmacology

The efficacy of the present compounds can be determined as describedbelow. The exemplified pharmacological assays, have been carried outwith the compounds of the present invention and their pharmaceuticallyaccepted salts.

In Vitro Model Exhibiting Insulin Resistance (IR Assay) Example 51 Theassay was designed as in the reference, British Journal of Pharmacology,130, 351-58, 2000, the disclosure of which is incorporated by referencefor the teaching of the assay.

The solution of test compound (10 μM/mL) was prepared in DMSO.

Rosiglitazone (0.1 μM in DMSO) was used as standard.

Differentiation into adipocytes was induced by the known methods asdescribed below. (See, also, J. Biol. Chem., 260, 2646-2652, 1985, thedisclosure of which is incorporated by reference for the teaching ofadipocyte differentiation)

Culture medium containing 0.5 nM 1-methyl-3-isobutylxanthine (IBMX),0.25 μM dexamethasone, 5 μg/ml insulin (bovine/human), 10 mM HEPESbuffer and fetal bovine serum (FBS) 10% by volume in Dulbecco's modifiedEagle's medium (DMEM) was used for differentiation.

3T3 L1 fibroblasts were seeded in 24- or 6-well plates at a density of0.5-2×10⁴ cells/well and were allowed to reach maximal confluency.

The confluent fibroblasts were exposed to culture medium for 2 days.After this period, fresh culture medium (DMEM) containing only insulinwas used, 10% FBS was added and cultured for 4 days with change ofmedium every 2 days. After 7 days the cultures received DMEM containing10% FBS with no exposure to insulin. By the end of 8-10 days, more than95% of the cells have become differentiated into adipocytes.

The mature adipocytes were exposed to dexamethasone, 100 nM added inethanol, in culture medium and incubated for 2 days. On the third day,solution of test compound was added along with 100 nM dexamethasonecontaining medium for 4 days with a change in medium after every 2 days.Vehicle control contained 1% v/v of DMS. Rosiglitazone was used as astandard and a was added at a concentration of 0.1 μM in DMSO, alongwith 100 nM dexanethasone containing medium for 4 days with a change inmedium after every 2 days. After a total period of 6 days, the cellswere processed for glucose uptake as follows.

The insulin resistant adipocytes were exposed to serum-free DMEMcontaining 0.1% bovine serum albumin for 3-4 hours at 37° C. in CO₂atmosphere. The test compound was also present during this period. After3-4 hours, the medium was aspirated and replaced with Kreb's Ringerphosphate (KRP) buffer at pH 7.4 and with human/porcine insulin, 200 nM.The cells were incubated for 30 minutes at 37° C. At the end of 30minutes, 0.05 or 0.1 μCi of ¹⁴C-2-deoxyglucose was added to each well ofeither 24- or 6-well plates respectively and was incubated for exactlyminutes. After exactly 5 minutes, the plates were transferred to icetrays and medium was rapidly aspirated. The cell layer was washed twicewith ice-cold phosphate buffered saline, (PBS), pH 7.4. Finally the celllayer was lysed with 150 μl of 0.1% sodium dodecyl sulfate (SDS) and theradioactivity of the cell lysate was determined in liquid scintillationcounter. Non-specific glucose uptake was assayed in wells exposed tocytochalasin B, inhibitor of glucose transport. Compounds that showedstatistically significant increase in the glucose transport/uptakeexpressed as CPM/well above the level in cells exposed to insulinvehicle are considered actives in this assay. The cut off limit foractivity in this IR assay was defined as the increase 1.50 fold ofvehicle, assay value of 1.0 for vehicle. Activity was also expressed as% of Rosiglitazone, which is used as a standard for comparison.Statistical analysis was performed using unpaired t-test.

The results are summarized in Table 1.

TABLE 1 Activity of compounds in insulin resistance model Sr. Compoundof % of No. example No. Fold activity* Rosiglitazone** Rosiglitazone2.60 ± 0.1  100 01 1 2.41 ± 0.06 78.75 ± 3.55 02 3 2.30 ± 0.16   52 ±6.5 03 5 2.41 ± 0.12 55.1 ± 4.8 04 13 1.40 ± 0.07  19.5 ± 3.51 05 151.70 ± 0.02 45.25 ± 1.04 06 16 1.60 ± 0.13 38.47 ± 7.98 07 17 1.26 ±0.02 21.20 ± 1.5  08 18 1.77 ± 0.10  65 09 19 1.67 ± 0.13    50 ± 10.1210 20 2.40 ± 0.68  36.7 ± 0.96 11 22 1.76 ± 0.58 15.8 ± 1.8 12 24 1.80 ±0.32  46.2 ± 23.8 13 26 2.19 ± 0.09 66.48 ± 5.26 14 27 2.01 ± 0.23    57± 15.64 15 28 2.60 ± 0.17 71.77 ± 7.48 16 29 2.01 ± 0.09   76 ± 6.11 1730 1.84 ± 0.02  62.51 ± 1.0..12 18 33 2.58 ± 0.11 68.59 ± 4.81 19 341.70 ± 0.08 43.59 ± 4.77 20 35 2.44 ± 0.08 67.36 ± 3.51 21 45 2.13 ±0.04  59.5 ± 2.26 22 48 1.82 ± 0.13 36.7 ± 7.3 *fold activity overvehicle **comparison with Rosiglitazone

Conclusion:

Representative compounds of the present invention showed insulinsensitizing activity in increasing glucose uptake in the insulinresistance model.

Example 52 (a) Human PPARγ Transactivation Assay

The assay was designed as in the reference, Biochem. Biophys. Res. Comm.175:865-871, 1991, the disclosure of which is incorporated by referencefor the teaching of the assay.

Human PPARγ activity was evaluated by transactivation using a luciferasereporter gene. The pBL-TK-luciferase reporter plasmid AOX-3×PPRE-TIK-LUCcontains three copies of the rat acyl CoA oxidase PPRE cloned upstreamof the minimal herpes simplex virus thymidine kinase (TK) promoter.Human full length PPARγ cDNA was cloned into pSG5 expression vector(Stratagene, Lo Jolla, Calif.).

HEK293 cells were seeded in 24 well plates and grown in DMEMsupplemented with 10% (v/v) FCS. After 24 hours, they were transfectedwith 100 ng of hPPARγ receptor and 300 ng of AOX-3X PPRE-ILUC reporterconstruct per well using Fugen 6 transfection reagent (Roche,Indianapolis, Ind.). Test compounds or Rosiglitazone (dissolved in DMSO)were added 24 hours after transfection. The control was 0.1% DMSO. After48 hours, transactivation activity was determined by luciferase assayusing Steady Glow reagent (Promega, Madison, Wis.). The results aresummarized in Table 2.

TABLE 2 Activity of Compound 1 in human PPAR transactivation assayCompound of PPARγ activity example No. (% of rosiglitazone)Rosiglitazone 100  1 23 26 19.3

(b) Mouse PPARγ Assay

The assay was designed as in the reference, Blood, 104(5),1361-8, 2004,the disclosure of which is incorporated by reference for the teaching ofthe assay.

3T3-L1 fibroblasts were seeded in 6-well plates at a density of 4×10⁴cells/well and cultured in DMEM containing 10% calf serum. After 4-5days, when the cells become confluent, each of test compound was added(from a 20 mM stock in DMSO) to the final concentration of 50 μM in DMEMsupplemented with 10% FCS. Rosiglitazone was added (from 10 mM stock) toa final concentration of 10 μM. The plates were incubated for 72 hrs at37° C. in a CO₂ incubator with fresh medium containing test substancesadded after first 48 hrs. After 72 hrs, the medium was removed; the celllayer was washed and processed for the PPARγ assay as per theinstruction of the manufacturer (Active Motif, North America,California, USA). PPARγ activation was determined using 96-well ELISAassay as per the instruction manual (TransAM PPARγ. Active Motif, Cat0.40196). Assay Readout was absorbance output from spectrophotometer forthe mouse PPARγassay. Luminescence data output was recorded for thehuman PPARγ assay.

The activity of a compound was expressed as relative activity comparedto Rosiglitazone, the reference compound used as positive control. Theresults are summarized in Table 3.

TABLE 3 Activity of Compound 1 in Mouse PPAR assay PPARγ activityCompound of example No. (% of rosiglitazone) Rosiglitazone 100  1 12.415 0 16 18.85 17 12.57 30 8.18 34 8.17

Conclusion:

In the selectivity assays for human and mouse PRARγ, che compounds ofthe present invention did not exhibit any PPARγ activation.

In Vivo Biological Experiments

Note: All animal experimental procedures were approved by Animal EthicsCommittee.

Compounds which were found active in example 51 were subjected to invivo evaluation in animal models of insulin resistance.

Example 53 Screening in db/db BL/6J mice

The protocol was designed as in references.

-   1. Metabolism, 53(12), 1532-1537, 2004.-   2. American journal of Hypertension, 17(5), Supplement 1, S32, 2004.

The disclosures of these two references are incorporated by referencefor the teaching of the protocol.

The screening of compounds was based on their ability to reduce theplasma glucose levels in genetically diabetic db/db BL/6J mice.

Male db/db mice (obtained from the Animal House of Nicholas PiramalResearch Centre, Goregaon, Mumbai, India) were used for this study (bodyweight in the range of 30-40 g and age is 6-8 weeks) and were kept eightper cage in individually ventilated cages at controlled temperature(22±1° C.) and humidity (45±5%). Food and water were provided ad libitumduring their laboratory stay, except for four hours fasting prior toblood sample collection. 12 hours light and dark cycle was followedduring the whole study period.

After 4 hours fasting blood samples were collected from mice. Miceshowing plasma glucose levels between 300 to 500 mg/dl were divided ingroups (8-10 per group) such that the mean plasma glucose levels andvariation within the group, for each group, is nearly same. Aftergrouping, mice in respective groups received treatment with 0.5% CMCvehicle, standard compound or test compounds for 10 days. Rosiglitazonewas used as a standard.

After 4 hours fasting, mice were anaesthetized using isoflurane(inhalation anesthetic), and blood samples were collected through theretro orbital plexus. Collected blood samples were centrifuged at 7000rpm for 10 minutes at 4° C.; Separated plasma was used for estimation ofplasma glucose using diagnostic kits (Diasys, Germany). Plasma glucoselevels of treated groups were normalized with control group using thefollowing formula, which accounted for the changes in control group.

Formula used for normalization was

*: {1−(Ratio of mean plasma glucose levels of control group on day 10 today 0)/(Ratio of plasma glucose levels of treated group on day 10 to day0)}×100.

The results are summarized in Table 4.

TABLE 4 Reduction in the plasma glucose levels in genetically diabeticdb/db BL/6J mice Compounds tested in db/db mice Com- pound ofRosiglitazone tested in exam- db/db mice Sr. ple Dose Normalization DoseNormalization No No. (10 days) with control* (10 days) with control* 011 150 mpk od 43.2 ± 15.7 10 mpk od 93.8 ± 22.7 02 24 150 mpk od Inactive10 mpk od 55.0 ± 11.4 03 26 100 mpk bid 41.90 ± 3.84   5 mpk 54.52 ±4.92  bid 04 30  50 mpk bid 76.2 ± 19.2  5 mpk 107.9 ± 15.1  bid 05 34 50 mpk bid 57.2 ± 19.1  5 mpk 83.6 ± 12.8 bid Formula used fornormalization: *{1 − (Ratio of mean plasma glucose levels of controlgroup on day 10 to day 0)/(Ratio of plasma glucose levels of treatedgroup on day 10 to day 0)} × 100

Conclusion: Representative compounds of present invention showedsignificant glucose lowering activity in the animal model of diabetes.

Example 54 Evaluation of Lipid Levels (Dyslipidemia)

The assay was designed as in the reference, Metabolism, 49 (1), 22-31,2000, the disclosure of which is incorporated by reference for theteaching of the assay.

Seven groups of male db/db mice (8 animals per group) were used. Animalswere orally dosed twice a day (bid) for an extended period of fifteendays, with either the vehicle or compound 1 (5 mpk, 25 mpk, 50 mpk, 100mpk and 200 mpk) or with the standard drug, Rosiglitazone (5 mpk). Bodyweight was measured daily. On day 15, the animals were deprived of foodfor 4 hours after the last dose administration. Blood was collected atthe end of the 4-hour period using heparinised capillaries by aretro-orbital puncture. Plasma samples were analyzed for glucose,triglyceride, cholesterol, using the autoanalyser.

Compound of example no. 1 exhibited triglyceride-lowering ability indb/db mice at all the doses tested. The compound caused plasmatriglyceride reductions ranging from 28%, to 42% with the higher dosesinducing higher reduction. Rosiglitazone, in the same study caused 40%decrease in plasma triglyceride levels.

Compound of example no. 1 tested at doses higher than 50 mpk, induced26% reduction in cholesterol levels. Rosiglitazone lowered cholesterollevels by a similar extent of 27%.

Conclusion: In db/db mice, Compound of example no. 1 was as efficaciousas Rosiglitazone, in lowering lipid levels.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of general formula (I) or a pharmaceutically acceptablesalt thereof, the general formula (I) being represented by:

wherein: Ar is a quinoline moiety which is substituted or unsubstituted;B is —O—; R¹ is hydrogen or S(O)₂R⁴; R² is S(O)₂R⁴, C(O)R⁵, orC(O)(CH₂)_(n)—C(O)OR⁶; R³ is halogen, cyano, C(O)OR⁷, or C(O)NR⁸R⁹; R⁴is substituted or unsubstituted aryl; R⁵ is (C₁-C₆)alkyl or substitutedor unsubstituted aryl; R⁶ is hydrogen, (C₁-C₄)alkyl, or substituted orunsubstituted aryl; R⁷ is hydrogen or (C₁-C₄)alkyl; R⁸ and R⁹ areindependently hydrogen or (C₁-C₆)alkyl; and n is an integer from 1-3. 2.The compound according to claim 1; wherein: Ar is a quinoline moietywhich is substituted or unsubstituted; B is —O—; R¹ is H; R² is S(O)₂R⁴;R³ is chlorine; and R⁴ is phenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl,2-chloro-4-trifluoromethylphenyl, 3-fluoro-4-methylphenyl,3-chloro-4-methylphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl,2,5-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl,4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,3,4-difluorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,2-fluoro-4-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl,2-chloro-4-trifluoromethylphenyl, 3-chloro-4-methylphenyl,2-chloro-4-fluorophenyl), 4-cyanophenyl, phenyl-3-carboxylic acid[phenyl-3-COOH], or 4-acetamidophenyl [(CH₃CONH-phenyl].
 3. The compoundaccording to claim 2; wherein: Ar is quinolin-3-yl; B is —O—; R¹ is H;R² is —S(O)₂R⁴; R³ is chlorine; and R⁴ is phenyl, 4-methylphenyl,3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 3-fluoro-4-methylphenyl,2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxyphenyl,4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 3,4-difluorophenyl, 4-chlorophenyl,2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2-chloro-4-trifluoromethylphenyl, or 2-fluoro-4-chlorophenyl.
 4. Thecompound according to claim 2; wherein: Ar is quinolin-6-yl; B is —O—;R¹ is H; R² is —S(O)₂R⁴; R³ is chlorine; and R⁴ is 3,4 dimethoxyphenyl,2,4-difluorophenyl, or 2,4-dichlorophenyl.
 5. The compound according toclaim 1; wherein: Ar is a quinoline moiety which is substituted orunsubstituted; B is —O—; R¹ is S(O)₂R⁴; R² is S(O)₂R⁴; R³ is halogen;and R⁴ is substituted aryl.
 6. The compound according to claim 5;wherein: Ar is quinolin-3-yl; B is —O—; R¹ is S(O)₂R⁴; R² is S(O)₂R⁴; R³is chlorine; and R⁴ is 2,4-dichlorophenyl.
 7. The compound according toclaim 1; wherein: Ar is a quinoline moiety which is substituted orunsubstituted; B is —O—; R¹ is H; R² is C(O)OR⁵; R³ is halogen; and R⁵is (C₁-C₆)alkyl or substituted or unsubstituted aryl.
 8. The compoundaccording to claim 7; wherein: Ar is quinolin-3-yl; B is —O—; R¹ is H;R² is C(O)OR⁵; R³ is chlorine; and R⁵ is phenyl.
 9. The compoundaccording to claim 1; wherein: Ar is a quinoline moiety which issubstituted or unsubstituted; B is —O—; R¹ is H; R² isC(O)(CH₂)_(n)—C(O)OR⁶; R³ is halogen; R⁶ is hydrogen, (C₁-C₄)alkyl, orsubstituted or unsubstituted aryl; and n is an integer from 1-3.
 10. Thecompound according to claim 9; wherein: Ar is quinolin-3-yl; B is —O—;R¹ is H: R² is C(O)(CH₂)₂—C(O)OR⁶; R³ is chlorine; and R⁶ is hydrogen.11. The compound according to claim 1; wherein the compound is selectedfrom:N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide;2,4-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methylbenzenesulfonamide;3,4-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide;N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-dimethoxybenzenesulfonamide;N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethoxy)benzenesulfonamide;2-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-(trifluoromethyl)benzenesulfonamide;N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-2,4-difluorobenzenesulfonamide;N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-fluorobenzenesulfonamide;4-Chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-difluorobenzenesulfonamide;N-(5-(Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,6-difluorobenzenesulfonamide;3,5-Dichloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3-fluoro-4-methylbenzenesulfonamide:N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,5-dimethylbenzenesulfonamide;N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-1)-2,4,6-trimethylbenzenesulfonamide;4-chloro-N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2-fluorobenzenesulfonamide;N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide;2,4-Dichloro-N-(5-chloro-6-(quinolin-6-yloxy)pyridin-3-yl)benzenesulfonamide;N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide;N-(5-Chloro-6-(quinolin-6-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide;2,4-Dichloro-N-[(2,4-dichlorophenyl)sulfonyl]-N-[5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl]-benzenesulfonamide;Phenyl 5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylcarbamate; and4-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-ylamino)-4-oxobutanoic acid.12. The compound according to claim 1; wherein the compound is selectedfrom:N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-4-methoxybenzenesulfonamide,N-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-3,4-dimethoxybenzenesulfonamide;andN-(5-Chloro-6-(quinolin-3-yloxy)pyridin-3-yl)-2,4-difluorobenzenesulfonamide.13. A process for the preparation of a compound of general formula (I)according to claim 1, the general formula (I) being represented by:

wherein: Ar is a quinoline moiety which is substituted or unsubstituted;B is —O—; R³ is halogen, cyano, C(O)OR⁷ or C(O)NR⁸R⁹; R⁷ is hydrogen or(C₁-C₄)alkyl; R⁸ and R⁹ are independently hydrogen or (C₁-C₆)alkyl; R¹is H; R² is S(O)₂R⁴; and R⁴ is substituted or unsubstituted aryl;wherein the process comprises: a) reacting a compound of general formula(II) with a compound of formula (III), in presence of a base, to obtaina compound of general formula (IV); wherein the general formula (II)isrepresented by:

wherein:  Hal is fluorine, chlorine, bromine, or iodine; and  R³ is asdefined above; wherein the formula (III) is represented by: Ar—BH;wherein Ar and B are as defined above; and wherein the general formula(IV) is represented by:

wherein Ar, B, and R³ are as defined above; b) subjecting the nitrocompound of formula (IV) above to reduction to obtain a correspondingamino compound of general formula (V):

wherein Ar, B, and R³ are as defined above; and c) reacting the aminocompound of general formula (V) with one equivalent of Hal-SO₂R⁴, in thepresence of a base, to obtain the compound of formula (I); wherein: Halis fluorine, chlorine, bromine, or iodine; and R⁴ is as defined above;and d) optionally, converting the resulting compound into apharmaceutically acceptable salt.
 14. A process for the preparation of acompound of general formula (I) according to claim 1, the generalformula (I) being represented by:

wherein: Ar is a quinoline moiety which is substituted or unsubstituted;B is —O—; R³ is halogen, cyano, C(O)OR⁷, or C(O)NR⁸R⁹; R⁷ is hydrogen or(C₁-C₄)alkyl; R⁸ and R⁹ are independently hydrogen or (C₁-C₆)alkyl; R¹and R² are S(O)₂R⁴; and R⁴ is substituted or unsubstituted aryl; whereinthe process comprises: a) reacting a compound of general formula (II)with a compound of formula (III), in presence of a base, to obtain acompound of general formula (IV); wherein the general formula (II) isrepresented by:

wherein:  Hal is F, Cl, Br, or I; and  R³ is as defined above; whereinthe formula (III) is represented by: Ar—BH wherein Ar and B are asdefined above; wherein the general formula (IV) is represented by:

wherein Ar, B, and R³ are as defined above; b) subjecting the nitrocompound of formula (IV) above to reduction to obtain a correspondingamino compound of general formula (V):

wherein Ar, B, and R³ are as defined above; and c) reacting the aminocompound of general formula (V) with two equivalents of Hal-SO₂R⁴ at 45°C., in the presence of triethyl amine as a base, to obtain the compoundof formula (I); wherein: Hal is fluorine, chlorine, bromine, or iodine;and R⁴ is as defined above; and d) optionally, converting the resultingcompound into a pharmaceutically acceptable salt.
 15. A process for thepreparation of a compound of general formula (I) according to claim 1,the general formula (I) being represented by:

wherein: Ar is a quinoline moiety which is substituted or unsubstituted;B is —O—; R³ is halogen, cyano, C(O)OR⁷, or C(O)NR⁸R⁹; R⁷ is hydrogen or(C₁-C₄)alkyl; R⁸ and R⁹ are independently hydrogen or (C₁-C₆)alkyl; R¹is H; R² is C(O)(CH₂)_(n)—C(O)OR⁶; n is an integer from 1-3; and R⁶ ishydrogen, (C₁-C₄)alkyl, or substituted or unsubstituted aryl, whereinthe process comprises: a) reacting a compound of general formula (II)with a compound of formula (III) in presence of cesium carbonate as abase, to obtain a compound of general formula (IV); wherein the generalformula (II) is represented by:

wherein: Hal is fluorine, chlorine, bromine, or iodine; and R³ is asdefined above, wherein the formula (III) is represented by: Ar—BH;wherein Ar and B are as defined above; wherein the general formula (IV)is represented by:

wherein Ar, B, and R³ are as defined above; b) subjecting the nitrocompound of formula (IV) above to reduction to obtain a correspondingamino compound of general formula (V):

wherein Ar, B, and R³ are as defined above; and c) refluxing the aminocompound of the general formula (V) above with an anhydride[(CH₂)_(n)(CO)₂O] to obtain an acid of formula (I); and d) optionally,converting the acid of formula (I) to an ester of formula (I); wherein:R² is C(O)(CH₂)_(n)—C(O)OR⁶; n is an integer from 1-3; and R⁶ is(C₁-C₄)alkyl or substituted or unsubstituted aryl; and e) optionally,converting the resulting acid or ester into a pharmaceuticallyacceptable salt.
 16. A process for the preparation of a compound ofgeneral formula (I) according to claim 1, the general formula (I) beingrepresented by:

wherein: Ar is a quinoline moiety which is substituted or unsubstituted;B is —O—; R³ is halogen, cyano, C(O)OR⁷ or C(O)NR⁸R⁹; R⁷ is hydrogen or(C₁-C₄)alkyl; R⁸ and R⁹ are independently hydrogen or (C₁-C₆)alkyl; R¹is H; R² is C(O)OR⁵; and R⁵ is (C₁-C₆)alkyl or substituted orunsubstituted aryl; wherein the process comprises: a) reacting acompound of general formula (II) with a compound of formula (III), inpresence of cesium carbonate as a base, to obtain a compound of generalformula (IV); wherein the general formula (II) is represented by:

wherein:  Hal is fluorine, chlorine, bromine, or iodine; and  R³ is asdefined above; wherein the formula (III) is represented by: Ar—BH;wherein Ar and B are as defined above; wherein the general formula (IV)is represented by:

wherein Ar, B, and R³ are as defined above; b) subjecting the nitrocompound of formula (IV) to reduction to obtain a corresponding aminocompound of general formula (V):

wherein Ar, B, and R³ are as defined above; and c) refluxing the aminocompound of general formula (V) with R⁵-carbonochloridate, in thepresence of pyridine or triethyl amine as a base, to obtain the compoundof formula (I): wherein R⁵ is as defined above; and d) optionally,converting the resulting compound into a pharmaceutically acceptablesalt.
 17. A pharmaceutical composition, comprising: a therapeuticallyeffective amount of a compound of general formula (I) according to claim1, or a pharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier or diluent.
 18. A pharmaceutical composition,comprising: a therapeutically effective amount of a compound of generalformula (I) according to claim 1, or a pharmaceutically acceptable saltor thereof; at least one further pharmaceutically active compound; and apharmaceutically acceptable carrier or diluent.
 19. A method for thetreatment of a metabolic disorder related to insulin resistance orhyperglycemia, comprising: administering to a mammal in need thereof atherapeutically effective amount of a compound of formula (I) accordingto claim 1, or a pharmaceutically acceptable salt thereof.
 20. Themethod according to claim 19; wherein the metabolic disorder related toinsulin resistance or hyperglycemia is selected from: type 2 diabetes,obesity, glucose intolerance, dyslipidemia, hyperinsulinemia,atherosclerotic disease, polycystic ovary syndrome, coronary arterydisease, hypertension, and non alcoholic fatty liver disease.
 21. Themethod according to claim 20; wherein the metabolic disorder related toinsulin resistance or hyperglycemia is type 2 diabetes.
 22. The methodaccording to claim 20; wherein the metabolic disorder related to insulinresistance or hyperglycemia is dyslipidemia.